histone deacetylases (HDACs) deacetytyped not only histones, which generally increase transcription and gene expression, but also other proteins such as thermal shock proteins (HSP90), alpha tubulin, some steroid receptors and many transcription factors (NF-kB p65, SP1, etc.). HDACs are thus involved in the control of many cellular processes. HDACs (or HDACi) inhibitors, together with their ability to induce cell differentiation and apoptose, are among the most promising anti-canceous drugs being developed for the treatment of solid and haematological neoplasias. Recently, the anti-inflammatory and immuno-modulating activity of HDACi has been successfully identified and exploited for the treatment of autoimmune diseases in pre-clinical models. As the effect of HDACi on the innate immune response remains largely unknown, we have undertaken the first major study in this area. In a first article, we demonstrate that HDACi inhibits the expression of many genes (microbial receptors, cytokines, chemiokines, adhesion molecules and co-stimulators, growth promoters, etc.) involved in in vitro anti-infective defences. In line with these data, HDACi increase mortality of infected animals in benign pneumonia and candidosis models. Similarly, HDACi protect animals from toxic and septic shock induced mortality by inhibiting the exuberant inflammatory response that characterises these conditions (Roger T. et al., Blood 2011). To further characterise HDACi’s influence on innate immune response, we also analysed the impact of two HDACi, valproic acid (VPA) and trichostatin A (TSA), on the main antimicrobial defences of macrophages. In a second article (Mombelli et al., Journal of Infectious Diseases 2011), we report that VPA and TSA reduce the capacity of macrophages to phagocyter and destroy gram-positive bacteria Staphylococcus aureus and Gram-negative Escherichia coli. In accordance with these data, HDACi inhibits the expression of molecules involved in phagocytosis such as spurious receptors (MSR 1 and CD14) and lectin type receptors (Dectin 1), as well as opsonine receptors (integrins). In addition, HDACi interfere with the expression of different sub-units of NADPH oxidase (gp91p "ox, p22 phox, p47 phox, p40 phox, p67 phox and Rac2) and nitric oxide (NO) inductible synthesised (iNOS), which are responsible for the production of oxygenated (ROS) and nitrogenated (NO) derivatives essential for the destruction of microorganisms in phagolysosome. In summary, this study describes mechanisms whereby HDACi reduce the ability to ingest and destroy bacteria, thereby increasing susceptibility to infections. Overall, our data indicate that HDACi are powerful anti-inflammatory drugs that could support infections in cancer patients treated with these drugs, as also appears to be suggested in clinical studies reported in the literature. We offer strict infectious clinical follow-up in patients treated with these agents.